1. Field of the Invention
The present invention pertains to novel, potent anticonvulsants, antiepileptics, analgesics and cognition enhancers achieving their action through the antagonism of specific excitatory amino acid (EAA) neurotransmitter receptors. In particular, the invention is directed to .omega.-[2-(phosphonoalkylenyl)cycloalkyl]-2-aminoalkanoic acids, their pharmaceutically acceptable salts and derivatives, and to the methods of synthesizing the same.
2. Description of the Prior Art
While L-glutamate and L-aspartate were initially thought merely to participate in brain metabolism, sufficient molecular pharmacological, biochemical and electrophysiological evidence now exists to suggest that these amino acids are neuroexcitatory transmitters [D. R. Curtis, A. W. Duggar, D. Felix, G. A. R. Johnston, A. K. Tebecis and J. C. Watkins. Brian Res., 41, 283-301 (1972)].
For many years following the initial characterization of the neuro-excitotoxic actions of amino acids, it was tacitly assumed that all compounds of this type (agonists and antagonists) acted upon the same receptor. The discovery of relatively selective antagonists of different actions of EAAs or of actions of different EAA compounds, has changed this perception, and it is now accepted that multiple recognition sites for EAAs are present in the vertebrate central nervous system[J. C. Watkins and R. H. Evans. Ann. Rev. Pharmacol. Toxicol., 21, 165-204 (1981)]. Defined by prototypical agonists or antagonists, these include:
1. receptors activated by L-glutamate (Glu) and the conformationally restricted Glu analog, quisqualic acid (Quis), and antagonized selectively by glutamic acid diethylester,
2. receptors responsive to the synthetic analogue of L-aspartate (Asp), N-methyl-D-aspartate (NMDA), the isoxazole neurotoxin, quniolinic acid (Quin) and, probably, to Asp itself. These receptors are antagonized by D-(-)-2-amino-5 phosphonopentanoic acid (AP5), D(-)-2-amini-7-phosphonoheptanoic acid (AP7), and the divalent cation, Mg.sup.++,
3. receptors activated by the pyrrolidine neuroexcitotoxin, kainic acid (KA), for which no specific antagonists have yet been identified and,
4. receptors antagonized by L-(+)-2-amino-4-phosphonobutyric acid (LAP4). Originally indentified as an EAA antagonist by electrophysiological means, LAP4 inhibits the response at the lateral perforant pathway synapses of the hippocampus to an unidentified endogenous excitatory substance. The possibility that Glu is this neurotransmitter is minimal and recent evidence suggests that the N-blocked dipetide, N-acetylaspartyl-L-glutamate may function in this capacity [J. M. H.ff-French-mullen, K. J. Koller, R. Zaczek, Li Hori, J. T. Coyle and D. O. Carpenter. Proc. Natl. Acad. Sci. U.S.A., 82, 3897-4001 (1985)].
Beyond these fundamental receptor categories, it has become increasingly apparent that subdivisions may exist within each receptor category. For example, receptors for NMDA appear to be pharmacologically distinct in different regions of the brain [T. W. Stone and J. H. Connick, Neuroscience, 15, 597-617 (1985)] and one subpopulation of NMDA receptors may be allosterically linked to the site of action of the dissociative anesthetics, phencyclidine and certain benz(F)isoquinolines. The novel tricyclic anticonvulsant MK801 may effect its primary action via an allosteric modulation of NMDA receptors [H. F. Wong et al. Proc. Natl. Acad. Sci. U.S.A., 83, 7104-7108 (1986)].
EAA's possibly acting through one or more of these receptors, have been implicated in the etiology of various pathological conditions affecting the CNS. Thus, KA [K. Biziere, J. T. Slevin, R. Zaczek, J. F. Collins and J. T. Coyle. In: Advances In Pharmacology and Therapeutics: H. Yoshida, Y. Hagihara and S. Ebashi, eds.; Pergamon, New York, 1982; pp 271-276], NMDA [R.Zaczek, J. Collins and J. T. Coyle. Neurosci, Letts., 24, 181-186 (1981)] and the endogenous EAA, Quin [R. Schwarcz, W. O. Whetsell and R. M. Mango. Science, 219, 316-318 (1983)], have been used to produce in animals a syndrome analogous to human epilepsy; the anatomical and neurochemical lesions and deficiencies produced by these compounds in animals are similar to the characteristics seen postmortem in the brains of patients dying with Huntington's disease [J. Coyle, and R. Schwarcz. Nature, 263, 244-246 (1976)] and epilepsy. Kainate administration can produce a limbic structure lesion that mimicks Ammon's Horn Sclerosis, an abnormality frequently found in temporal lobe epilepsy. Research on this model of temporal lobe epilepsy has suggested the endogenous EAA's may play a role in this disorder that is particularly resistant to existing antiepileptics [J. V. Nadler, B. W. Perry, C. W. Cotman. Nature, 271, 676-677 (1981)]. In addition to Huntington's disease and epilepsy, it has been suggested that EAA's may contribute to ALzheimer's disease [A. C. Foster, J. F. Collins and R. Schwarcz. Neuropharmacology, 22, 331-1341 (1983)], E. Roberts. In: Strategies for the development of an Effective Treatment of Senile Dementia: (E. Crook and L. Gershon, eds.; Mark Power Assoc: New Camarin, Conn. 1981; pp 247-230], the neuronal death following stroke and other instances of cerebral ischemia, [R. P. Simon, J. H. Swan, T. Griffiths and B. S. Meldrum. Science, 226, 850-852 (1984): S. Rothman. J. Neuroscience, 4, 1884-1891 (1984)] and hereditary olivopontocerebellar atrophy [J. T. Coyle, TINS, 5, 287-288 (1982)]. Additionally, the growing recognition of an association between NMDA receptors and the dissociative anesthetics which are functional antagonists of NMDA suggests that NMDA receptor antagonists may elicit antinociceptive responses. Should this be substantiated, such compounds would represent an entirely novel category of analgesics since unlike currently available drugs which are universally receptor agonists, the analgesic properties of compounds acting at NMDA receptors would be elicited through receptor blockade.
Because of the conceptual link between EAAs activity at specific brain receptors in vivo, excitotoxic lesions caused by EAA in animals, the pathogenesis of the above neurodegenerative diseases including the dementias, and the the potential application of EAA antagonists for uses such as antinociception, it is logical to explore pharmacologic means to antagonize endogenous excitatory and/or excitotoxic neurotransmitters. The development of antagonists of exogenous excitotoxins such as KA is also logical, since there is presumably and yet undiscovered specific endogenous substance that acts at brain KA receptors. The advent of potent and selective antagonists of EAA's exemplified by .alpha.-amino-.omega.-phosphonoalkylenylcarboxylic acids (the most potent and selective being D(-)2-amino-7-phosphonoheptanoic acid, D(-)AP7) has provided a point of departure for the pharmacologic intervention of EAA action at their receptors.
Besides interferring with the neurotoxic and convulsive actions of NMDA, the exogenous excitotoxin, IBO, and the endogenous excitotoxin Quin (but not KA) [A. C. Foster, J.F. Collins and R. Schwarcz. Neuropharmacology, 22, 1331-1341 (1983): R. Schwarcz, F.J. Collins and D. A. Parks. Neurosci. Letts., 33, 85-90 (1982)], AP7 (i.c.v. and i.v.) protects against audiogenically-induced seizures in genetically susceptible mice [M. J. Croucher, J. F. Collins and B. S. Meldrum. Science, 216, 899-901 (1982)]. I.v. AP7 suppresses photically-induced myoclonus in the baboon [B. S. Meldrum, M. J. Croucher, G. Badman and J. F. Collins. Neurosi. Letts., 39, 101-104 (1983)], increased threshold current for electroshock-induced seizures of mice and prevents chemically-induced seizures in rodents [S. J. Czuczwar and G. Meldrum. Eur. J. Pharmacology, 83, 335-338 (1982)]. Very recently, AP7 (intrahippocampally) has been reported to markedly reduce or eliminate ischemic brain damage in the rodent carotid artery occlusion model of stroke [R. P. Simon, J. H. Swan, T. Griffiths and B. S. Meldrum. Science, 226, 850-852 (1984)], and another, less potent, EAA antagonist .delta.-D-glutamyl glycine, has been shown to protect cultured rat hippocampal neurones from degeneration under conditions of oxygen depletion while blocking the toxicity of exogenously applied Glu and Asp [S. Rothman. J. Neuroscience, 4, 1884-1891 (1984)]. Mixed KA and Quis receptor antagonists have also been shown to possess anticonvulsant activity [M. J. Croucher, B. S. Meldrum, A. W. Jones and J. C. Watkins. Brain Res., 377, 111-114 (1984)]. Finally, and significantly, several lines of circumstantial evidence link EAAs, especially Glu, with the onset of age-associated neurodegenerative diseases, including Alzheimer's disease [J. T. Greenamyre, J. B. Penney, A. B. Yound, C. D'Amato, S. P. Hicks, I. Schoulson. Science, 227, 1496-1498 (1985)], and with tardive dyskinesia [J. W. Olney. In: Excitotoxins K. Fuxe, R. Roberts, and R. Schwarcz, eds].